Challenging recommended oral and intravenous voriconazole doses for improved efficacy and safety: population pharmacokinetics-based analysis of adult patients with invasive fungal infections.

BACKGROUND: Recommended oral voriconazole (VRC) doses are lower than intravenous doses. Because plasma concentrations impact efficacy and safety of therapy, optimizing individual drug exposure may improve these outcomes. METHODS: A population pharmacokinetic analysis (NONMEM) was performed on 505 plasma concentration measurements involving 55 patients with invasive mycoses who received recommended VRC doses. RESULTS: A 1-compartment model with first-order absorption and elimination best fitted the data. VRC clearance was 5.2 L/h, the volume of distribution was 92 L, the absorption rate constant was 1.1 hour(-1), and oral bioavailability was 0.63. Severe cholestasis decreased VRC elimination by 52%. A large interpatient variability was observed on clearance (coefficient of variation [CV], 40%) and bioavailability (CV 84%), and an interoccasion variability was observed on bioavailability (CV, 93%). Lack of response to therapy occurred in 12 of 55 patients (22%), and grade 3 neurotoxicity occurred in 5 of 55 patients (9%). A logistic multivariate regression analysis revealed an independent association between VRC trough concentrations and probability of response or neurotoxicity by identifying a therapeutic range of 1.5 mg/L (>85% probability of response) to 4.5 mg/L (<15% probability of neurotoxicity). Population-based simulations with the recommended 200 mg oral or 300 mg intravenous twice-daily regimens predicted probabilities of 49% and 87%, respectively, for achievement of 1.5 mg/L and of 8% and 37%, respectively, for achievement of 4.5 mg/L. With 300-400 mg twice-daily oral doses and 200-300 mg twice-daily intravenous doses, the predicted probabilities of achieving the lower target concentration were 68%-78% for the oral regimen and 70%-87% for the intravenous regimen, and the predicted probabilities of achieving the upper target concentration were 19%-29% for the oral regimen and 18%-37% for the intravenous regimen. CONCLUSIONS: Higher oral than intravenous VRC doses, followed by individualized adjustments based on measured plasma concentrations, improve achievement of the therapeutic target that maximizes the probability of therapeutic response and minimizes the probability of neurotoxicity. These findings challenge dose recommendations for VRC.

Oral valganciclovir prophylaxis in kidney transplant recipients

Background: Immunosuppressive and antivira[ prophy[ actic drugs are needed to prevent acute rejection and infection after organ transplantation. We assessed the effectiveness of a new combined regimen introduced at our transplantation center. Methods: We reviewed at[ consecutive patients who underwent kidney transplantation at our institution over a 5.5-year period, with a follow-up of at [east 6 months. Patients transplanted from 1/2000 to 3/2003 (Period 1) were compared to patients transplanted from 4/2003 to 7/2005 (Period 2). In period 1, patients were treated with Basi[iximab, Cic[osporin, steroids and Mycophenotate or Azathioprine. Prophylaxis with Va[acic[ ovir was prescribed in CMV D+/R- patients; otherwise, a preemptive antivira[ approach was used. In period 2, immunosuppressive drugs were Basi[- iximab, Tacro[imus, steroids and Mycopheno[ate. A 3-month CMV prophylaxis with Va[gancic[ovir was used, except in D-/R- patients. Results: Sixty-three patients were transplanted in period 1 and 70 patients in period 2. Baseline characteristics of both groups were comparable; in particular 17% of patients were CMV D+/R- in period 1 compared to 23% in period 2 (p=0.67). Acute rejection was more frequent in period 1 than in period 2 (40% of patients vs 7%, respectively p<0.001). Nineteen patients (30%) in period 1 were diagnosed with CMV infection/disease that required treatment, compared with 8 patients (11.4%) in period 2 (p = 0.003). Of these 8 patients, at[ had CMV infection/disease after discontinuation of Va[gancic[ovir prophylaxis, 6 were D+/R- (75%), and at[ were treated with oral Va[gancic[ovir. There was no difference between periods in terms of incidence of BK nephropathy, post-transplant [ymphopro[ iferative disease, graft toss, and mortality. Conclusions: These results indicate that a 3-month course of oral Va[gancic[ovir is very effective to prevent CMV infection/disease in kidney transplantation. Late-onset CMV disease is a residual problem in D+/R- patients receiving VGC prophylaxis.

Gender based-violence at Universities

Estudi realitzat a partir d’una estada al Center for Lifelng Learning de l’ University of Warwick, entre 2006 i 2008. Aquesta recerca es centra en l'estudi del fenomen de la violència de gènere a les universitats. Recerques prèvies ens indiquen que la violència de gènere afecta a tot tipus de dones, de totes les cultures, edats, estatus professionals i nivells educatius. També es constata que aquesta violència no només es dóna en l'àmbit domèstic, sinó també en diferents àmbits socials, incloses les institucions educatives. La literatura científica sobre aquesta temàtica de països com Estats Units o Canadà ha incidit en com també trobem aquest fenomen en els contextos universitaris. A Europa s'ha fet molt poca recerca centrada en analitzar la violència de gènere que afecta a les dones a les universitats. Amb aquest estudi s'ha explorat la literatura científica existent a nivell mundial sobre aquesta temàtica, s'ha analitzat el tractament d'aquesta problemàtica a nivell de legislacions i recomanacions institucionals, principalment a nivell de l'Estat espanyol, de Catalunya i d'organismes internacionals, i s'han analitzat pràctiques en el tractament d'aquesta problemàtica en diferents universitats del Regne Unit. Per altra banda, s'ha incidit en l'estudi del impacte que diferents formes de violència de gènere té en els processos formatius i en els projectes professionals de dones a les universitats. Així mateix, s'han analitzat elements claus de pràctiques a les universitats del Regne Unit en la implementació de polítiques contra l'assetjament sexual que afecta a les dones. La identificació d'aquests elements s'orienta a aportar recomanacions claus per a la implementació de mesures orientades a la prevenció i la superació de diferents formes de violència que afecta a les dones a les universitats.

Violència contra les dones: anàlisi de la situació psicològica personal i interpersonal d'un grup de dones maltractades

Aquest projecte és la continuació d'un estudi pilot finançat per l'Institut Català de les Dones (U/01-6). Es va anar incrementant la grandària de la mostra -avaluant les característiques del maltractament, la simptomatologia, la personalitat i la seva percepció de la relació de parella-, fins que el 2003 -i gràcies a l'ajut del Departament de Benestar i Família-, dins la Fundació Vidal i Barraquer es va crear un servei d'assistència pública especialitzat en atendre dones maltractades (UNADOM); lloc on durant el 2006 hem desenvolupat el treball que ara presentem. L'objectiu general d'aquest estudi transversal consistia en analitzar la situació psicosocial d'un grup de dones maltractades que acudien a la UNADOM, afegint com a element novedós l'avaluació dels estils d'enfrontament que les dones fan servir després de l'experiència abusiva viscuda. Els instruments utilitzats són l'MCMI-II (Millon, 1999), la DAS (Spanier, 1976), el COPE (Carver et al., 1989) i una adaptació de l’Entrevista Semiestructurada sobre Maltractament Domèstic (Echeburúa et al., 1994). Es recull informació d'un total de 50 dones, 17 de les quals han completat la mesura sobre l'enfrontament. Els resultats indiquen que les escales de personalitat que apareixen més alterades són l'esquizoide, la dependent i l'evitativa, i que aquestes són coherents amb les actituds defensives i les estratègies d'enfrontament predominants de les dones de la mostra. A nivell clínic, i segons l’experiència assistencial, es conclou amb la importància de realitzar entrevistes exploratòries acurades ja que això facilita la indicació terapèutica més adient i la focalització de l'ajuda.

Modernització d'un equip de DTA per a mesures d'estabilitat tèrmica de polímers

L’objectiu del projecte ha estat modernitzar un equip d’anàlisi tèrmica diferencial (DTA) realitzant un programa informàtic mitjançant Labview per programar un controlador PID Eurotherm model 3216 d'un forn NETZSCH 6.231.0 i adquisició de dades mitjançant targeta NI-9211. S’ha comprovat que el programa informàtic funciona correctament realitzant assaigs d'anàlisi tèrmic diferencial d'alguns polímers. El programa i cada un dels equips s’han implementat en el laboratori, s’ha calibrat el sistema i s’han realitzat diversos assaigs experimentals comprovant el seu correcte funcionament. S’han repetit els assaigs per comprovar la reproducibilitat i s’han comparat els resultats amb gràfics realitzats amb altres equips comprovant la correlació dels resultats obtinguts. Es fa constar que no és objectiu d’aquest projecte optimitzar la senyal ni l’estudi de propietats de les mostres assajades sinó comprovar el correcte funcionament del programa informàtic creat per controlar el forn i adquirir dades.

Donor's and organ representations in liver, kidney, heart and lung transplantation : a qualitative longitudinal study

Purpose: Organ transplantation is a biological and psychological challenge and graft acceptance is an important achievement for patients. Patients' concerns toward the deceased donor and the organ may contribute to this process. Method: Forty-seven patients involved in heart (N=9), liver (N=8), lung (N=14) and kidney (N=16) transplantation participated in IRB-approved longitudinal semi-structured interviews: (T1) registered on the waiting-list, (T2) six months and (T3) twelve months after transplantation. Qualitative pattern analysis (QUAPA) was carried out on the verbatim transcripts and concerns about the donor and the organ were then analysed. Results: - Donor's representation: At T1, patients were reluctant to talk about the donor: 27% expressed culpability and 19% accepted the clause of anonymity. At T2, intense emotions were associated with the reminiscing about the donor and 45% highlighted the generosity of his/her act. In addition, heart, lung and kidney recipients were concerned about the donor's identity: 42% challenged the clause of anonymity. Liver recipients complained about anonymity, but could nevertheless cope with it. At T3, 47% of heart, lung and kidney recipients thought daily of the donor and 33% were still looking for information about him/her. Liver recipients rarely have thoughts about the donor. - Organ representation: At T1, organ descriptions were biomedical (49% of the interviewees) and more rarely, mainly heart candidates, referred to the symbolic meaning of the organ. After transplantation (T2-T3), function was underlined. Acceptance and organ integration were associated with post-operative outcomes (23%) and psychological well-being (45%). Some patients (32%) inferred the donor's personality from the organ quality and felt privileged having received an organ in such a good state. Conclusion: Donor's representations should be explored during the transplantation process as they play an important role in the psychological acceptance of the graft.

Hepatitis C Virus Infection and Kidney Transplantation in 2014: What's New?

Chronic hepatitis C virus (HCV) infection remains an important health problem, which is associated with deleterious consequences in kidney transplant recipients. Besides hepatic complications, several extrahepatic complications contribute to reduced patient and allograft survival in HCV-infected kidney recipients. However, HCV infection should not be considered as a contraindication for kidney transplantation because patient survival is better with transplantation than on dialysis. Treatment of HCV infection is currently interferon-alpha (IFN-α) based, which has been associated with higher renal allograft rejection rates. Therefore, antiviral treatment before transplantation is preferable. As in the nontransplant setting, IFN-free treatment regimens, because of their greater efficacy and reduced toxicity, currently represent promising and attractive therapeutic options after kidney transplantation as well. However, clinical trials will be required to closely evaluate these regimens in kidney recipients. There is also a need for prospective controlled studies to determine the optimal immunosuppressive regimens after transplantation in HCV-infected recipients. Combined kidney and liver transplantation is required in patients with advanced liver cirrhosis. However, in patients with cleared HCV infection and early cirrhosis without portal hypertension, kidney transplantation alone may be considered. There is some agreement about the use of HCV-positive donors in HCV-infected recipients, although data regarding posttransplant survival rates are controversial.

Are the high-growth recovery periods over?

We present evidence about the loss of the so-called "plucking effect", that is, a high-growth phase of the cycle typically observed at the end of recessions. This result matches the popular belief, presented informally by different authors, that the current recession will have permanent effects, or that the current recession will have an L shape versus the old-time recessions that have always had a V shape. Furthermore, we show that the loss of the "plucking effect" can explain part of the Great Moderation. We postulate that these two phenomena may be due to changes in inventory management brought about by improvements in information and communications technologies.

New estimates for the maximal singular integral

"Vegeu el resum a l'inici del document del fitxer adjunt."

Consumers’ sensory acceptability of pork from immunocastrated male pigs

Boar taint is the off-odour or off flavour of cooked pork. Currently, the most common method of controlling boar taint is surgical castration. However, immunocastration has been used in some parts of the world as an alternative to surgical castration. The aim of this study was to evaluate the sensory acceptability of meat from immunocastrated pigs (IM) compared with meat from females (FE), surgically castrated (CM) and entire males (EM). Twenty animals of each type were evaluated by 201 consumers in 20 sessions. Longissimus thoracis muscle of the different animals was cooked in an oven at 180 °C for 10 min. Consumers scored the odour and the flavour of the meat in a 9-point category scale without an intermediate level. There were no significant differences in consumer’s evaluation of meat from IM, CM, and FE. In contrast, EM meat presented a higher percentage of dissatisfied scores and was significantly (P & 0.05) less accepted than meat from CM, IM and FE. Consumers’ acceptability of EM meat was always lower, independently of its androstenone levels. However meat with low levels of androstenone was more accepted that meat with medium or high levels of this substance. It can be concluded that immunocastration produced pork that was accepted by the consumers, and was indistinguishable from pork from CM or FE.

Sharp weighted bounds for fractional integral operators

The relationship between the operator norms of fractional integral operators acting on weighted Lebesgue spaces and the constant of the weights is investigated. Sharp bounds are obtained for both the fractional integral operators and the associated fractional maximal functions. As an application improved Sobolev inequalities are obtained. Some of the techniques used include a sharp off-diagonal version of the extrapolation theorem of Rubio de Francia and characterizations of two-weight norm inequalities.

La ramaderia ecològica de boví a les Valls d'Àneu i viabilitat del producte ecològic: de la producció al consum

A les Valls d’Àneu la producció ramadera de boví ecològic és molt important, ja que, actualment, el 22% de les explotacions són ecològiques i es preveu que aquest percentatge augmenti fins al 50% en els propers dos anys. Malgrat això, la motivació principal per a convertir les explotacions convencionals en ecològiques és el factor econòmic, no la consciència ambiental. En l’anàlisi del cicle productiu carni del boví ecològic procedent de les Valls d’Àneu s’ha observat que no hi ha diferències substancials entre la producció ecològica i la convencional. Tot i així, el producte carni de boví ecològic no té gran sortida al mercat, ja que aquest és incipient i, a més, el preu del producte ecològic és molt més elevat que el del convencional. Un aspecte crític de la producció ramadera ecològica és que la seva normativa no considera els impactes ambientals que genera, com són els derivats del transport, la generació de residus d’envasos, etc. En aquest estudi es presenta una aproximació quantitativa dels impactes generats en el cicle productiu carni de boví ecològic de les Valls d’Àneu.

Exome sequencing extends the phenotypic spectrum for ABHD12 mutations: from syndromic to nonsyndromic retinal degeneration.

OBJECTIVE: To identify the genetic causes underlying autosomal recessive retinitis pigmentosa (arRP) and to describe the associated phenotype. DESIGN: Case series. PARTICIPANTS: Three hundred forty-seven unrelated families affected by arRP and 33 unrelated families affected by retinitis pigmentosa (RP) plus noncongenital and progressive hearing loss, ataxia, or both, respectively. METHODS: A whole exome sequencing (WES) analysis was performed in 2 families segregating arRP. A mutational screening was performed in 378 additional unrelated families for the exon-intron boundaries of the ABHD12 gene. To establish a genotype-phenotype correlation, individuals who were homozygous or compound heterozygotes of mutations in ABHD12 underwent exhaustive clinical examinations by ophthalmologists, neurologists, and otologists. MAIN OUTCOME MEASURES: DNA sequence variants, best-corrected visual acuity, visual field assessments, electroretinogram responses, magnetic resonance imaging, and audiography. RESULTS: After a WES analysis, we identified 4 new mutations (p.Arg107Glufs*8, p.Trp159*, p.Arg186Pro, and p.Thr202Ile) in ABHD12 in 2 families (RP-1292 and W08-1833) previously diagnosed with nonsyndromic arRP, which cosegregated with the disease among the family members. Another homozygous mutation (p.His372Gln) was detected in 1 affected individual (RP-1487) from a cohort of 378 unrelated arRP and syndromic RP patients. After exhaustive clinical examinations by neurologists and otologists, the 4 affected members of the RP-1292 had no polyneuropathy or ataxia, and the sensorineural hearing loss and cataract were attributed to age or the normal course of the RP, whereas the affected members of the families W08-1833 and RP-1487 showed clearly symptoms associated with polyneuropathy, hearing loss, cerebellar ataxia, RP, and early-onset cataract (PHARC) syndrome. CONCLUSIONS: Null mutations in the ABHD12 gene lead to PHARC syndrome, a neurodegenerative disease including polyneuropathy, hearing loss, cerebellar ataxia, RP, and early-onset cataract. Our study allowed us to report 5 new mutations in ABHD12. This is the first time missense mutations have been described for this gene. Furthermore, these findings are expanding the spectrum of phenotypes associated with ABHD12 mutations ranging from PHARC syndrome to a nonsyndromic form of retinal degeneration.

Tolerance-inducing immunosuppressive strategies in clinical transplantation: an overview.

The significant development of immunosuppressive drug therapies within the past 20 years has had a major impact on the outcome of clinical solid organ transplantation, mainly by decreasing the incidence of acute rejection episodes and improving short-term patient and graft survival. However, long-term results remain relatively disappointing because of chronic allograft dysfunction and patient morbidity or mortality, which is often related to the adverse effects of immunosuppressive treatment. Thus, the induction of specific immunological tolerance of the recipient towards the allograft remains an important objective in transplantation. In this article, we first briefly describe the mechanisms of allograft rejection and immune tolerance. We then review in detail current tolerogenic strategies that could promote central or peripheral tolerance, highlighting the promises as well as the remaining challenges in clinical transplantation. The induction of haematopoietic mixed chimerism could be an approach to induce robust central tolerance, and we describe recent encouraging reports of end-stage kidney disease patients, without concomitant malignancy, who have undergone combined bone marrow and kidney transplantation. We discuss current studies suggesting that, while promoting peripheral transplantation tolerance in preclinical models, induction protocols based on lymphocyte depletion (polyclonal antithymocyte globulins, alemtuzumab) or co-stimulatory blockade (belatacept) should, at the current stage, be considered more as drug-minimization rather than tolerance-inducing strategies. Thus, a better understanding of the mechanisms that promote peripheral tolerance has led to newer approaches and the investigation of individualized donor-specific cellular therapies based on manipulated recipient regulatory T cells.

El sistema de abreviaturas en el Diccionario académico: Introducción (1726), institucionalización (1770) y consolidación (1780). La marcación del léxico específico

En aquest treball s’analitza la introducció d’abreviatures en el Diccionario de la Real Academia Española, especialment les relacionades amb el lèxic específic, en la 1ª edició d’Autoridades (1726), en la incompleta 2ª edició d’Autoridades (1770) i en la 1ª ed. del DRAE (1780). Després de l’anàlisi, es manifesta la modernitat de la 2ª edició d’Autoridades (1770), ja que institucionalitza un sistema amb abreviatures diatècniques que arriba fins ara i influeix en nombrosos diccionaris. A més a més, es comprova que la 1ª ed. del DRAE (1780) consolida i amplia aquest recurs.